Role of Nitric Oxide in apoptosis
Apoptosis is a form of programmed cell death in which cells die in a controlled and regulated manner. There are a number of ways in which apoptosis can be triggered, including activation of death receptors such as Fas or TRAIL, cellular stresses leading to release of cytochrome C from the mitochondria, DNA damage and viral infection.
NO regulates apoptosis in wide range of cell types, although its precise effects are dependent on the amount of NO used and the type of cell. It has been shown to both induce and inhibit apoptosis. Nitric oxide has been demonstrated to inhibit apoptosis in a number of cell types including leukocytes, hepatocytes, trophoblasts and endothelial cells.
The illustration below shows some of the ways in which NO can inhibit apoptosis induced through the death receptors.
Nitric oxide is able to affect apoptotic signalling at multiple points in the pathway:
1) NO can regulate the expression of the death receptors in a cGMP dependent manner
2) NO can alter the expression of protein such as acid sphingomyelinase that help regulate the early signalling events in death receptor signalling such as ceramide production. This reduces DISC (Death Inducing Signalling Complex) formation and is also mediated through the production of cGMP.
3) The activity of the caspases can be directly affected by NO through nitrosylation of the active site, leading to inhibition of protein function.
4) The effect of NO on caspase activity and DISC formation leads to reduced cleavage of Bid and therefore a lack of amplification of apoptotic signalling through the mitochondria.
5) NO can also affect the expression of many members of the Bcl-2 protein family, including both pro- and anti-apoptotic proteins. This can affect the release of cytochrome C and other factors from the mitochondria and is mediated through the production of cGMP.
6) DISC formation can also be affected through the recruitment of the anti-apoptotic protein cFLIP. One of the proteins that can affect cFLIP recuitment to the DISC is PKC and the activity of PKC can be regulated by NO through nitrosylation.
Generally the anti-apoptotic effects of NO can be mediated through a number of mechanisms such as the nitrosylation and inactivation of many of the caspases including caspase 3, caspase 1 and caspase 8. Other mechanisms include activating p53, upregulating heat shock protein 70 (and consequently blocking recruitment of pro-caspase 9 to the Apaf-1 apoptosome), upregulating Bcl-2 and Bcl-XL (with subsequent inhibition of cytochrome C release from the mitochondria) and activating cGMP signaling leading to activation of cGMP-dependent protein kinases and suppression of caspase activity.
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